Schizophrenia is a psychiatric diagnosis that describes a mental illness characterised by impairments in the perception or expression of reality, most commonly manifesting as auditory hallucinations, paranoid or bizarre delusions or disorganised speech and thinking in the context of significant social or occupational dysfunction.
Onset of symptoms typically occurs in young adulthood (Castle et al. 1965), with approximately 0.4-0.6% of the population affected (Goldner et al. 2002). Diagnosis is based on the participant's self-reported experiences and observed behaviour. Schizophrenia occurs equally in males and females although it typically appears earlier in men with the peak ages of onset being 20-28 years for males and 26-32 years for females. Much rarer are instances of childhood-onset and late- (middle age) or very-late-onset (old age) schizophrenia.
The lifetime prevalence of schizophrenia, that is, the proportion of individuals expected to experience the disease at any time in their lives, is commonly given at 1%.
Schizophrenia is known to be a major cause of disability. In a 1999 study of 14 countries, active psychosis was ranked the third-most-disabling condition after quadriplegia and dementia, and before paraplegia and blindness (Robson et al. 2014).
Studies suggest that genetics, early environment, neurobiology and psychological and social processes are important contributory factors. Current psychiatric research is focused on the role of neurobiology, but no single organic cause has been found. Due to the many possible combinations of symptoms, there is debate about whether the diagnosis represents a single disorder or a number of discrete syndromes.
Schizophrenia is often described in terms of positive (or productive) and negative (or deficit) symptoms (Sims, 2002). Positive symptoms include delusions, auditory hallucinations, and thought disorder, and are typically regarded as manifestations of psychosis. Negative symptoms are so-named because they are considered to be the loss or absence of normal traits or abilities, and include features such as flat or blunted affect and emotion, poverty of speech (alogia), anhedonia, and lack of motivation (avolition).
Despite the appearance of blunted affect, recent studies indicate that there is often a normal or even heightened level of emotionality in schizophrenia, especially in response to stressful or negative events (Cohen and Docherty, 2004).
A third symptom grouping, the disorganisation syndrome, is commonly described, and includes chaotic speech, thought, and behaviour. There is also evidence for a number of other symptom classifications. The disorder is also thought to affect cognition, which also usually contributes to chronic problems with behaviour and emotion.
People diagnosed with schizophrenia are likely to be diagnosed with comorbid conditions, including clinical depression and anxiety disorders; the lifetime prevalence of substance abuse is typically around 40%. Social problems, such as long-term unemployment, poverty and homelessness, are common and life expectancy is decreased; the average life expectancy of people with the disorder is 10 to 12 years less than those without, owing to increased physical health problems and a high suicide rate.
Social isolation commonly occurs and may be due to a number of factors. Impairment in social cognition is associated with schizophrenia, as are the active symptoms of paranoia from delusions and hallucinations, and the negative symptoms of apathy and avolition. Many people diagnosed with schizophrenia avoid potentially stressful social situations that may exacerbate mental distress (Freeman et al. 2007).
Late adolescence and early adulthood are peak years for the onset of schizophrenia. These are critical periods in a young adult's social and vocational development, and they can be severely disrupted by disease onset.
Schizophrenia has three phases: prodromal, active and residual. These phases tend to happen in order and appear in cycles throughout the course of the illness. During a lifetime, people with schizophrenia may become actively ill once or twice, or have many more episodes.
In the prodromal phase, people start to lose interest in their usual activities and to withdraw from friends and family members. They may become easily confused, have trouble concentrating, and feel listless and apathetic, preferring to spend most of their days alone. They may also become intensely preoccupied with religion or philosophy. This phase can last weeks or months.
During schizophrenia's active phase, people may have delusions, hallucinations, marked distortions in thinking and disturbances in behaviour and feelings. This phase is often the most frightening to the person with schizophrenia, and to others.
After an active phase, people may be listless, have trouble concentrating and be withdrawn. The symptoms in this residual phase are similar to those that occur during the prodromal phase.
To minimise the effect of schizophrenia, much work has recently been done to identify and treat the prodromal (pre-onset) phase of the illness, which has been detected up to 30 months before the onset of symptoms, but may be present longer (Addington et al. 2007). Those who go on to develop schizophrenia may experience the non-specific symptoms of social withdrawal, irritability and dysphoria in the prodromal period, and transient or self-limiting psychotic symptoms in the prodromal phase before psychosis becomes apparent (Robson et al. 2014).
Increased dopaminergic activity in the mesolimbic pathway of the brain is a consistent finding in schizophrenia. The mainstay of treatment to date has been focussed on pharmacotherapy with antipsychotic medications; these primarily work by suppressing/regulating dopamine activity.
A fundamental barrier to the discovery and development of novel treatments for schizophrenia has been the level of understanding of the biological processes involved in schizophrenia which, to date, has not been sufficient to predict the therapeutic value of novel drug targets. This lack of understanding has limited the ability to develop effective treatments to address the negative symptoms and cognitive impairment of schizophrenia.
The introduction into clinical practice of chlorpromazine in the mid-1950s revolutionised the treatment of the psychotic manifestations of schizophrenia and triggered the development of dozens of alternative antipsychotic medications.
A decade or so later, the synthesis of clozapine and the unanticipated discovery of its antipsychotic effects led in time to a new ‘second generation’ cohort of drugs that lacked the characteristic unwanted extrapyramidal effects of the ‘typical’ antipsychotic medications.
The pharmacological profiles of the many ‘atypical’ drugs currently available vary widely, but it remains the case that all of them rely primarily for their efficacy upon their effects at the dopamine D2 receptor (Miyamoto et al. 2005).
Approximately one third of first episode psychosis participants fail to respond adequately to a standard typical or atypical antipsychotic medication, and non-responders have been found to incur health costs that are twice those of responders. Recent analyses suggest little if any difference in overall efficacy between the typicals and atypicals.
Clozapine stands alone in its ability to produce a therapeutic response in participants resistant to all other antipsychotics although the pharmacological mechanism by which it achieves this response remains unknown. Unfortunately its clinical utility is limited by its propensity to cause agranulocytosis and the consequent need for haematological monitoring, along with epileptic seizures and other serious unwanted effects (Lindstrom, 1998).
The endocannabinoid system (ECS), first discovered in the early 1990s, consists of cannabinoid receptors, endogenous ligands (‘endocannabinoids’), and proteins for endocannabinoid synthesis and degradation. Two G protein-coupled receptors for cannabinoids have so far been identified, designated cannabinoid receptor-1 (CB1) and cannabinoid receptor-2 (CB2).
CB1 receptors are located predominantly at the presynaptic terminals of central and peripheral neurons, their main role being to mediate inhibition of neurotransmitter release. However, they are also expressed in several peripheral structures not exclusively within nervous tissue including those controlling metabolism, hormone release (e.g. cortisol and adrenaline levels), and the immune response.
CB2 receptors are expressed mainly by immune cells, through which they modulate the release of both pro- and anti-inflammatory cytokines. Accumulating evidence suggests they may also be found in neurones.
This wide distribution of the receptors accounts for the breadth of influence of the ECS on immune response, learning, food intake, energy homeostasis, pain transduction, emotion, perception, behavioural reinforcement, motor co-ordination, regulation of body temperature and wake/sleep cycle, hormonal function, bone formation and apoptosis.
The activity of the ECS within the CNS is essential for normal mental health. CB1 receptors are densely expressed in the cortex, hippocampus, amygdala, basal ganglia, and cerebellum. Of relevance to schizophrenia, CB1 modulates release of dopamine and glutamate (as well as gamma-aminobutyric acid, serotonin, glycine, acetylcholine, and noradrenaline), and in participants their expression is increased in prefrontal cortex and anterior cingulate cortex. CB1 knockout mice show increased emotional reactivity, hypersensitivity to stress, reduced responsiveness to rewarding stimuli, increased aggression to intruders, enhanced development of learned helplessness, impaired extinction of aversive memories, and social withdrawal (Robson et al, 2014).
Raised levels of anandamide have been found in the cerebrospinal fluid of untreated schizophrenia participants in comparison with controls and participants with dementia or depression. Raised blood levels of anandamide have also been found in untreated schizophrenia participants, and these were reduced after clinical remission following olanzapine treatment (De Marchi et al. 2003). Although a strong case can be made for heightened ECS activity, the CB1 antagonist rimonabant had no effect on positive or negative symptoms of schizophrenia in a placebo-controlled clinical trial.
The cannabinoid cannabidiol, (CBD), appears to exhibit antipsychotic properties, and thus may be used in the treatment of schizophrenia, or more precisely the positive symptoms, namely hallucinations, delusions and confused thoughts (thought disorder).
An extensive review of the antipsychotic properties of CBD by Iseger et al. in 2015, which reviewed and referenced 29 studies incorporated by reference, concluded that CBD was an effective, safe and well tolerated antipsychotic compound, and thus may be a promising new agent in the treatment of schizophrenia.
It has been postulated that CBD may have potential utility in schizophrenia, not only as an antipsychotic but also in the alleviation of the metabolic and inflammatory abnormalities associated with the disease.
The negative symptoms of schizophrenia are discussed in detail in Foussias and Remington, 2010. The article explains that in the 1950's the introduction of chloropromazine revolutionised the treatment of major mental disorders, including schizophrenia, alleviating the positive symptoms (delusions/hallucinations) but it was not until the mid-70's early 80's that attention turned to the role of the deficit or negative symptoms.
Negative symptoms have been categorised into specific sub domains and many studies have focussed on the Scale for the Assessment of Negative Symptoms (SANS). SANS is a rating scale used to measure the negative symptoms in schizophrenia. The SANS scale consists of 5 subscales: (i) Affective flattening or blunting; (ii) Alogia; (iii) Avolition/apathy; (iv) Anhedonia/asociality; and (v) Attentional impairment.
It would be desirable to have drugs that could target these domains.
As well as negative symptoms, cognitive symptoms have been implicated as playing a substantial role in schizophrenia and both are evident at the time first episode psychosis occurs, and neither are improved substantially with existing antipsychotic treatments.
Thus, it would be desirable to have drugs that additionally targeted cognitive symptoms.
That negative and cognitive symptoms are separate domains is becoming apparent and the cognitive symptoms are generally regarded as comprising social cognition and neuro cognition and some of these aspects have traditionally been considered as/alongside negative symptoms (see for example Sergi et al. 2007).
The FDA has indicated that currently available drug treatments for schizophrenia have not been found to be satisfactory for the treatment of negative symptoms (Laughren and Levin, 2006).
It is noted that whilst almost all antipsychotic medications are targeted to the disease entity e.g. schizophrenia, as opposed to specific aspects of the disease, the FDA has now recognised that for complex psychiatric diseases there is a need to treat distinct aspects of the disease. Indeed the FDA has recently approved medications to be used in, for example, the treatment of “agitation” or “suicidality” in schizophrenia.
Furthermore they have endorsed the view that, for example “cognitive impairment” is a legitimate target in schizophrenia and that claims to a non-specific symptom not limited to a single disease entity would be appropriate.
A starting point for considering the claimed invention is WO 2009/087351, which discloses the use of cannabinoids in combination with an antipsychotic medicament. Generally it teaches that a number of phytocannabinoids (8 are specifically disclosed) may be used in combination with a number of antipsychotic medicaments (12 are specifically disclosed) to treat psychosis or a psychotic disorder (13 are specifically disclosed). The teaching is based on three lists (phytocannabinoid, antipsychotic medication and disease subsets) offering a total of 1,248 possible combinations. Of these combinations the detailed description exemplifies two specific combinations: CBD and aripiprazole; or THCV and aripiprazole, where the addition of the cannabinoid is for the purpose of improving the side effect profile of the aripiprazole by reducing catalepsy and ptosis.
A difference between WO 2009/087351 and the present invention is that it has been demonstrated, in human subjects, that providing cannabidiol (CBD) in combination with either olanzapine, aripiprazole or quetiapine (in contrast to 8 other antipsychotics) provided unexpected, and statistically significant outcomes, that could significantly improve treatments for a group of patients including those that may be considered to be treatment resistant.
Very significantly, the different technical effects achieved, enable new treatments to be offered. These new treatments include (but are not limited to): Targeting new patient groups (e.g. treatment resistant patients); Targeting a different phase of illness (e.g. prodromal, active or residual phase); Improving symptomatic relief (e.g. positive symptoms); Targeting different symptoms (e.g. negative symptoms (as opposed to positive symptoms); or Targeting specific domain subsets (e.g. Avolition/apathy, Anhedonia/asociality and disturbance of attention); or Providing a treatment or a combination medication that hits multiple targets (e.g. targets positive and/or negative symptoms and/or social cognition and/or neuro cognition).
A paper by Zuardi et al. (2010) describes the use of CBD in the treatment of two female patients with bipolar affective disorder. One patient was taking olanzapine as an adjunct therapy during the 30 days she was provided with CBD the other took CBD as a monotherapy. Zuardi states that CBD was ineffective in both patients with this disorder.
Taylor (2006) and Gururajan et al. (2012) describe the ability of CBD to reverse social deficits in rats treated with MK-801.
Deiana (2013) and Gomes et al. (2015) provide a review of the potential medical use of cannabidiol in the treatment of schizophrenia.